A Novel Approach for Characterization of Cathepsin D Protease and Its Effect on Tau and β-Amyloid Proteins

Malik, Mazhar N.; Fenko, Michael D.; Sheikh, Ashfaq M.; Wen, Gen; Li, Xiaohong

doi:10.1007/s11064-010-0395-9

Cited by 11 publications

(5 citation statements)

References 31 publications

(37 reference statements)

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“…They reported the presence of giant cathepsin D-positive compartments in the brain of transgenic mouse AD model. Cathepsin D was also detected in our MS analysis of the aggregates isolated from astrocytes lacking stefin B. Cathepsin D was found to be increased in other two mouse models of AD [54] and it was shown in vitro that it can cleave both tau, APP [55] and the Swedish mutant of APP [56], thus possibly generating the pathogenic Aβ42 fragment [57], [58]. However, the role of cathepsin D in AD is still controversial [59], [60].…”

Section: Discussionmentioning

confidence: 66%

Human Stefin B Role in Cell's Response to Misfolded Proteins and Autophagy

et al. 2014

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Alternative functions, apart from cathepsins inhibition, are being discovered for stefin B. Here, we investigate its role in vesicular trafficking and autophagy. Astrocytes isolated from stefin B knock-out (KO) mice exhibited an increased level of protein aggregates scattered throughout the cytoplasm. Addition of stefin B monomers or small oligomers to the cell medium reverted this phenotype, as imaged by confocal microscopy. To monitor the identity of proteins embedded within aggregates in wild type (wt) and KO cells, the insoluble cell lysate fractions were isolated and analyzed by mass spectrometry. Chaperones, tubulins, dyneins, and proteosomal components were detected in the insoluble fraction of wt cells but not in KO aggregates. In contrast, the insoluble fraction of KO cells exhibited increased levels of apolipoprotein E, fibronectin, clusterin, major prion protein, and serpins H1 and I2 and some proteins of lysosomal origin, such as cathepsin D and CD63, relative to wt astrocytes. Analysis of autophagy activity demonstrated that this pathway was less functional in KO astrocytes. In addition, synthetic dosage lethality (SDL) gene interactions analysis in Saccharomyces cerevisiae expressing human stefin B suggests a role in transport of vesicles and vacuoles These activities would contribute, directly or indirectly to completion of autophagy in wt astrocytes and would account for the accumulation of protein aggregates in KO cells, since autophagy is a key pathway for the clearance of intracellular protein aggregates.

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Section: Discussionmentioning

confidence: 66%

Human Stefin B Role in Cell's Response to Misfolded Proteins and Autophagy

et al. 2014

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“…Cathepsin D, the lysosomal protease profoundly expressed in the brain plays a paramount role in the regulation of cellular apoptosis thus contributing to the AD pathogenesis [29]. P2X 7 , a unique bifunctional purinoreceptor implicated in AD pathogenesis, induces membrane blebbing and cell death either by necrosis or apoptosis by opening a non selective cation channel or making a large, cytolytic pore based on agonist application [30].…”

Section: Pathological Apoptosismentioning

confidence: 99%

“…HN may protect against cognitive impairment, inflammatory response, apoptosis, Ab [25][26][27][28][29][30][31][32][33][34][35] [92], Ab 31-35 [93], in mouse or rat models of AD [12].…”

Section: Proteins and Peptidesmentioning

confidence: 99%

Apoptosis in Alzheimer’s Disease: An Understanding of the Physiology, Pathology and Therapeutic Avenues

2014

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Alzheimer's disease (AD) is a devastative neurodegenerative disorder with complex etiology. Apoptosis, a biological process that plays an essential role in normal physiology to oust a few cells and contribute to the normal growth, when impaired or influenced by various factors such as Bcl2, Bax, caspases, amyloid beta, tumor necrosis factor-α, amyloid precursor protein intracellular C-terminal domain, reactive oxygen species, perturbation of enzymes leads to deleterious neurodegenerative disorders like AD. There are diverse pathways that provoke manifold events in mitochondria and endoplasmic reticulum (ER) to execute the process of cell death. This review summarizes the crucial apoptotic mechanisms occurring in both mitochondria and ER. It gives substantial summary of the diverse mechanisms studied in vivo and in vitro. A brief account on neuroprotection of several bioactive components, flavonoids and antioxidants of plants against apoptotic events of both mitochondria and ER in both in vitro and in vivo has been discussed. In light of this, the burgeoning need to develop animal models to study the efficacy of various therapeutic effects has been accentuated.

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“…Finally, tau proteolysis by thrombin [95–97] and cathepsins [98–100] has also been described. Thrombin has been found in the AD brain associated with NFTs, as well as senile plaques [101].…”

Section: Inhibiting Proteolytic Processing Of Taumentioning

confidence: 99%

Therapeutic strategies for the treatment of tauopathies: Hopes and challenges

Khanna

Kovalevich

Lee

et al. 2016

Alzheimer's & Dementia

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A group of neurodegenerative diseases referred to as tauopathies are characterized by the presence of brain cells harboring inclusions of pathological species of the tau protein. These disorders include Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) due to tau pathology, including progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Tau is normally a microtubule-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from microtubules, with consequent misfolding and deposition into inclusions that mainly affect neurons, but also glia. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, and there is a growing interest in developing tau-directed therapeutic agents. The following review provides a summary of strategies under investigation for the potential treatment of tauopathies, highlighting both the promises and challenges associated with these various therapeutic approaches.

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A Novel Approach for Characterization of Cathepsin D Protease and Its Effect on Tau and β-Amyloid Proteins

Cited by 11 publications

References 31 publications

Human Stefin B Role in Cell's Response to Misfolded Proteins and Autophagy

Human Stefin B Role in Cell's Response to Misfolded Proteins and Autophagy

Apoptosis in Alzheimer’s Disease: An Understanding of the Physiology, Pathology and Therapeutic Avenues

Therapeutic strategies for the treatment of tauopathies: Hopes and challenges

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